Abstract
Treatment options for COVID‐19, caused by SARS‐CoV‐2, remain limited. Understanding viral pathogenesis at the molecular level is critical to develop effective therapy. Some recent studies have explored SARS‐CoV‐2–host interactomes and provided great resources for understanding viral replication. However, host proteins that functionally associate with SARS‐CoV‐2 are localized in the corresponding subnetwork within the comprehensive human interactome. Therefore, constructing a downstream network including all potential viral receptors, host cell proteases, and cofactors is necessary and should be used as an additional criterion for the validation of critical host machineries used for viral processing. This study applied both affinity purification mass spectrometry (AP‐MS) and the complementary proximity‐based labeling MS method (BioID‐MS) on 29 viral ORFs and 18 host proteins with potential roles in viral replication to map the interactions relevant to viral processing. The analysis yields a list of 693 hub proteins sharing interactions with both viral baits and host baits and revealed their biological significance for SARS‐CoV‐2. Those hub proteins then served as a rational resource for drug repurposing via a virtual screening approach. The overall process resulted in the suggested repurposing of 59 compounds for 15 protein targets. Furthermore, antiviral effects of some candidate drugs were observed in vitro validation using image‐based drug screen with infectious SARS‐CoV‐2. In addition, our results suggest that the antiviral activity of methotrexate could be associated with its inhibitory effect on specific protein–protein interactions.
Highlights
The ongoing global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) (Wu et al, 2020)
Remdesivir, an experimental drug that was originally investigated as a potent inhibitor of Ebola virus (EBOV) (Warren et al, 2016), was the first drug approved by the US Food and Drug Administration (FDA) for the treatment of COVID-19 in October 2020 (Rubin et al, 2020)
Some membrane proteins that are known as receptors or regulators of other coronaviruses, such as dipeptidyl peptidase 4 (DPP4) (Raj et al, 2013), aminopeptidase N (ANPEP) (Delmas et al, 1992), and interferon-inducible transmembrane proteins (IFITM1 and IFITM3) (Huang, Bailey, et al, 2011; Shi et al, 2021), may not directly bind to SARS-CoV-2 proteins, but can enhance viral entry (Fig 1A) (Li et al, 2020)
Summary
The ongoing global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) (Wu et al, 2020). The R&D activity to develop a vaccine or drug against COVID-19 is being fasttracked globally. By July 2021, 32 vaccines had reached phasethree clinical trials, and 11 were approved by at least one country (Dai & Gao, 2020; Creech et al, 2021). Vaccines are the primary means to prevent COVID-19, antiviral drugs would significantly reduce the disease burden for the early treatment of COVID19, and long COVID (Schmidt, 2021) suppression. Despite the controversy over whether remdesivir can reduce the duration of COVID-19, it is obvious that fully effective drugs for the prevention or treatment of SARS-CoV-2 are currently not available
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